Citric Acid → (S)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide

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Reaction Steps

A solution of 1-chloro-N,N,2-trimethylprop-1-en-1-amine (1.521 mL, 11.50 mmol) in DCM (2 mL) was added dropwise to a stirred solution of (S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropanoic acid (Intermediate C4c) (2.45 g, 10.45 mmol) in DCM (10 mL) over a period of 1 minute under nitrogen. The resulting pale yellow solution was stirred at ambient temperature for 30 minutes Anhydrous pyridine (1.262 mL, 15.68 mmol) was added in one portion (solution turns deeper yellow) followed by 3-methyl-1,2,4-thiadiazol-5-amine (CAS no. 17467-35-5) (1.204 g, 10.45 mmol) in DCM (3 mL) dropwise over a period of 1 minute. The resulting solution was stirred at ambient temperature for 1 hour. 1M citric acid (50 mL) added and extracted with EtOAc (50 mL). Organic phase washed with water (25 mL) and brine (25 mL), dried (MgSO4), filtered and evaporated. The residue was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in isohexane to afford (S)-2-(tert-butyldimethylsilyloxy)-3-methoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (390 mg, 11%). 1H NMR (400 MHz, CDCl3) δ 0.11 (6H, dd), 0.89 (9H, s), 2.49 (3H, s), 3.30 (3H, s), 3.61 (2H, t), 4.46 (1H, dd), 9.75-9.90 (1H, s); m/z (ESI+) (M+H)+=332.30; HPLC tR=2.77 min.

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